U.S. Pat. No. 5,382,600 discloses (substituted) 3,3-diphenylpropylamines useful for treating urinary incontinence. In particular, it discloses 2-[(1R)-3-(diisopropylamino)-1-phenylpropyl)-4-methylphenol, also known as N,N-diisopropyl-3-(2-hydroxy-5-methylphenyl)-3-phenylpropylamine, with the generic name of tolterodine, as being useful to treat urinary incontinence. Tolterodine is the compound of Example 22 of U.S. Pat. No. 5,382,600.
It is preferred that tolterodine is prepared by the processes of International Publication WO98/29402 (U.S. Pat. No. 5,922,914).
U.S. Pat. No. 5,559,269 and U.S. Pat. No. 5,686,464 disclose hydroxytolterodine and related compounds as being useful to treat urinary incontinence. Hydroxytolterodine is also the major metabolite of tolterodine (Nilvebrant et al, 1997, Eur J Pharmacol, 327:195–207).
The presence of an additional hydroxyl group in tolterodine increases its hydrophilic property. In an attempt to avoid this increase, WO 99/58478 discloses substituted 3,3-diphenylpropylamines for use as pharmaceutically active substances.
The international patent application WO 98/43942 discloses therapeutically active diarylpropylamines, which have favorable anticholinergic properties, and which can be used for the treatment of disorders related to urinary incontinence.
Gillberg et al, Eur J Pharmacol 349(2–3): 285–292 (1998) have suggested that decreased potency for a muscarinic antagonist at the m3 receptor may improve the ratio of desired effects at the bladder, relative to effects on the salivary glands that result in dry mouth. Thus, a selectivity for muscarinic M3/m3 over M2/m2 receptors may result in a more pronounced effect on salivation than on bladder contraction.
It has been observed that metabolism of 3,3-diphenylpropylamines occurs in vivo. This well-known phenomenon may be involved in increased drug clearance, diminished bioavailability, diminished half-life in vivo, drug interactions, and pharmacokinetic differences between subjects, depending on their drug metabolizing enzyme activities.
Postlind et al, Drug Metabolism and Disposition, 26(4): 289–293 (1993) disclose that tolterodine is metabolized by various cytochrome P450 enzymes. The two main metabolic events are oxidation of the 5-methyl group, catalyzed by the CYP2D6 enzyme, and dealkylation of the nitrogen, catalyzed by the CYP3A enzyme.
Thus, despite the above advances in the art, it is desirable to develop novel 3,3-diphenylpropylamines that are less prone to metabolism in vivo.